Psychological, pharmacological and developmental insights into the prefrontal circuits underlying threat regulation and negative bias in marmosets

作为个人，我们每天都面临着引发恐惧和焦虑的情况，无论是相对温和的，例如对一群人发表演讲，还是更严重的，例如失去工作的前景。轻微的恐惧和焦虑与我们的行为变化以及伴随的生理变化有关，包括心率增加，肌肉紧张和压力激素水平。这种情绪反应使我们能够适应特定的情况，并为我们做好准备，或者帮助我们避免负面事件。然而，如果不受调节和过度，这些反应会导致临床焦虑，这是焦虑症的核心症状（终生患病率为16%），但也可能是许多其他疾病的突出症状，包括抑郁症，强迫症和精神分裂症。不幸的是，潜在治疗的范围相对有限，治疗成功的水平也高度可变。例如，选择性5-羟色胺再摄取抑制剂（SSRIs）对某些人有效，而对另一些人来说，它们需要与去甲肾上腺素再摄取抑制剂（SNRIs）相结合才有益，而对另一些人来说，这两种治疗都无效。这种差异性的一个原因是，可能有各种各样的原因导致人们可能表现出临床焦虑，这些焦虑取决于不同大脑回路活动的变化。为了支持这一点，我们最近在动物身上发现，大脑中一个称为前额叶皮层的功能不同区域的活动增加或减少，类似于临床焦虑患者的活动，可以导致类似焦虑的行为和心血管反应增强，例如心跳加速。因此，这项研究的一个主要目的是区分心理缺陷，这些心理缺陷是由前额叶皮层这些不同区域的失调引起的焦虑样状态增强的基础。我们通过在各种行为测试中训练动物来实现这一目标，这些测试也可以在人类中进行研究，确保我们的发现可以转化为临床。我们将使用一种方法，使我们能够暂时激活或激活一个给定的大脑区域短时间内（约10分钟）。30分钟），并调查其在各种威胁引发的情况下的影响。如果我们能够区分不同人焦虑的不同潜在原因，这将有助于提供更好的诊断。第二个目的是确定可用于治疗人类焦虑症的不同类别的药物（例如SSRIs）对我们动物中由前额叶皮层不同区域的激活或失活诱导的焦虑样行为的影响。这将使我们能够确定不同的类别是否在改善这些可分离的焦虑样状态方面或多或少有效。这些研究的结果将有助于为制定针对患者的治疗策略铺平道路。最后，如果我们要充分了解临床焦虑，我们需要了解大脑回路是如何发展的，以及它们是如何受到压力的影响的，因为焦虑症通常出现在青春期，而幼儿期的压力是最重要的风险因素之一。人们对调节焦虑的复杂大脑回路是如何发展的知之甚少，因此通过使用发育期远短于人类的动物，我们可以在发育的关键阶段，包括儿童期和青春期早期和晚期，对个体的大脑进行成像。使用各种复杂的成像技术，我们的目标是确定这些大脑回路何时在整个发展过程中整合，以及整合中的个体差异如何与成年期焦虑样特征的个体差异相关。总之，这将告诉我们什么时候引起焦虑的电路可能最容易受到压力的影响。

As individuals we are faced with situations that provoke fear and anxiety on a daily basis, whether they be relatively mild, e.g. giving a talk to a group of people, or more serious, e.g. the prospect of losing one's job. Mild fear and anxiety are associated with changes in our behaviour and accompanying changes in our physiology, including increased heart rate, muscle tension and stress hormone levels. Such emotional responses allow us to adapt to a given situation and either prepare us for, or help us to avoid, a negative event. However, if unregulated and in excess, these responses lead to clinical anxiety, which is a core symptom of anxiety disorders (which have a lifetime prevalence of 16%) but can also be a prominent symptom of many other disorders, including Depression, Obsessive Compulsive disorder and Schizophrenia. Unfortunately, the range of potential treatments is relatively restricted and the level of treatment success, highly variable. For example, selective serotonin reuptake inhibitors (SSRIs) work for some people, while for others, they need to be combined with noradrenaline re-uptake inhibitors (SNRIs) to be beneficial and for still others, neither treatment is effective. One reason for this variability is that there are likely varied causes underlying why someone may show clinical anxiety that are dependent upon alterations in the activity of distinct brain circuits. In support of this, we have recently shown in animals that increases or decreases in the activity of functionally distinct areas within a region of the brain called the prefrontal cortex, similar to those seen in patients with clinical anxiety, can lead to enhanced anxiety-like behaviour and cardiovascular responses e.g. racing heart. One major aim of this research proposal therefore is to differentiate the psychological deficits that underlie the enhanced anxiety-like state induced by dysregulation of these distinct regions of prefrontal cortex. We achieve this by training animals on a variety of behavioural tests that critically, can also be studied in humans, ensuring our findings can be translated into the clinic. We will use a methodology that will allow us to temporarily inactivate or activate a given brain region for a short time period (approx. 30 minutes) and investigate its effects in a variety of threat-eliciting contexts. This will help provide better diagnosis if we can differentiate the distinct underlying causes of anxiety in different people. A second aim is to determine the effects of distinct classes of drugs that may be used to treat anxiety in humans e.g. SSRIs, on the anxiety-like behaviour in our animals induced by activations or inactivations of distinct regions of the prefrontal cortex. This will allow us to determine whether distinct classes are more or less effective in ameliorating these separable anxiety-like states. The results from these studies will help to pave the way for developing patient specific treatment strategies.Finally, if we are to fully understand clinical anxiety, we need to understand how brain circuits develop and how they are affected by stress, since anxiety disorders often emerge in adolescence, with stress in early childhood among the most significant risk factors. There is little understanding of how complex brain circuits involved in regulating our anxiety develop and so by using animals, in which the developmental period is far shorter than humans, we can image the brain of individuals at key stages across development, including childhood and early and late adolescence. Using a variety of sophisticated imaging techniques we aim to identify when these brain circuits become integrated across development and how individual differences in integration relate to individual differences in anxiety-like traits in adulthood. Together, this will inform our understanding of when the circuits that give rise to anxiety may be at their most vulnerable to stress.